Genetic variants in human sterol regulatory element binding protein-1c in syndromes of severe insulin resistance and type 2 diabetes
Genetic variants in human sterol regulatory element binding protein-1c in syndromes of severe insulin resistance and type 2 diabetes
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DOI：
10.2337/diabetes.53.3.842
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发表时间：
2004-03-01
期刊：
影响因子：
7.7
通讯作者：
O'Rahilly, S
中科院分区：
文献类型：
--
作者：
Laudes, M;Barroso, I;O'Rahilly, S
转录因子固醇调节元件结合蛋白(SREBP)-1c与脂类和糖代谢的调节密切相关。为了研究该基因突变是否可能导致胰岛素抵抗，我们在85名患有严重胰岛素抵抗的无关人类受试者中筛选了编码氨基末端转录激活域的外显子。两个错义突变(P87L和P416A)在单发患者中被发现，而在47名对照中未发现。然而，这些变异体在结合DNA或反式激活SREBP-1反应启动子的能力上与野生型没有区别。我们还发现了一种常见的内含子单核苷酸多态。(C/T)位于外显子18c和19c之间。在一项病例对照研究中，517名英国高加索病例受试者和517名年龄和性别匹配的对照组受试者中，该基因的T等位基因与男性2型糖尿病显著相关(优势比=1.42P=0.0015)，但与女性无关。在另一项对1100名高加索人进行的基于人群的单独研究中，T等位基因携带者的表现显著。总胆固醇和低密度脂蛋白水平升高(P
The transcription factor sterol regulatory element binding protein (SREBP)-1c is intimately involved in the regulation of lipid and glucose metabolism. To investigate whether mutations in this gene might contribute to insulin resistance, we screened the exons encoding the aminoterminal transcriptional activation domain, in a cohort of 85 unrelated human subjects with severe insulin resistance. Two missense mutations (P87L and P416A) were found in single affected patients but not in 47 control subjects. However, these variants were indistinguishable from the wild-type in their ability to bind DNA or to trangactivate an SREBP-1 responsive promoter construct. We also identified a common intronic single nucleotide polymorphism. (C/T) located between exon 18c and 19c. In a case-control study of 517 U.K. Caucasian case subjects and 517 age- and-sex-matched control subjects, the T-allele at this locus was significantly associated with type 2 diabetes in men (odds ratio=1.42 [1.11-1.82], P=0.0015) but not women. In a separate population-based study of 1,100 Caucasians, carriers of the T-allele showed significantly. higher levels of total and LDL cholesterol (P